This K01 award will support my development as an independent investigator with a translational research program that specializes in the cognitive and biological basis of neurodegenerative diseases such as frontotemporal lobar degeneration (FTLD). Candidate: My research experience as a cognitive neuroscientist ideally positions me to achieve my career goal of becoming an independent investigator with expertise on the cognitive and biological basis of neurodegenerative disease. I have strong cognitive training with an M.Sc in Psycholinguistics and Ph.D in Psychology from the University of Edinburgh, where I was supported by an NRSA Individual Predoctoral Award. During my postdoctoral IGERT fellowship at the Institute for Research in Cognitive Science at the University of Pennsylvania, I was awarded an NRSA Individual Postdoctoral Fellowship Award to investigate the role of decision-making in language. In this research I have gained experience investigating neurodegenerative disease patients comparatively in order to obtain converging evidence to complement fMRI studies of healthy adults. I have become increasingly interested in translating my research to optimize the diagnosis and treatment of patients with neurodegenerative diseases. I was recently award the Society for the Neurobiology of Language Postdoctoral Merit Award in recognition of my novel research investigating how social limitations in patients contribute to difficulty in discourse. I have committed to four years of clinical research the NIH Loan Repayment Program, and I intend to commit to clinical research for the duration of my career. I have learned that cognitive and neuroimaging studies provide only one perspective on neurodegenerative diseases. In this proposal, I plan to gain the necessary expertise in biological aspects of FTLD and related conditions to complement my past experiences, and thus achieve my goal of becoming a multifaceted independent investigator with expertise in the cognitive and biological basis for neurodegenerative diseases. With the support of this K01, I will develop expertise to conduct investigations of cerebrospinal fluid (CSF), genetic, and neuropathological aspects of neurodegenerative diseases. I will ultimately integrate the biological expertise gained in this proposal with language studies from my cognitive neuroscience research in an effort to identify non-invasive biomarkers that can be used to screen patients for clinical trials and to measure the efficacy of disease-modifying agents. Environment: This award will be conducted at the Perelman School of Medicine at the University of Pennsylvania in the Department of Neurology, the Center for Neurodegenerative Disease Research (CNDR), and the Penn Bioinformatics Center where I have strong institutional support. The proposed institution is an exceptional environment that has expert centers for neuroimaging, cerebrospinal fluid biomarker analysis, a leading genetic research core, expert neuropathology, outstanding biostatisical support, and relevant clinical research laboratories. The University of Pennsylvania is unique in comparison to other institutions in the country because all of the above methods are available in one center. My mentor, Dr. Murray Grossman, and my co-mentor, Dr. John Trojanowksi, have international reputations for neurodegenerative disease research. My career development will also be supported by my co-mentor, Dr. Lyle Ungar, who has extensive expertise in statistical learning algorithms and in the analysis of proteomic and genomics datasets. Together, this mentorship team will facilitate my development as an independent investigator by providing access to existing and future collaborators, laboratory resources, and exceptional training environments. The CNDR is a world- leading center for neurodegenerative disease research with human and animal models of disease and exceptional translational science. Biofluid biomarker experience is extensive, and several national biofluid cores are centered at Penn (e.g. ADNI). There is a wealth of internationally-recognized neuroimaging expertise at the University of Pennsylvania in the Penn Imaging and Computer Science Laboratory, and I will benefit by integrating neuroimaging resources from these facilities with other modalities of biomarker research. Training: I will develop my expertise in the biological basis of neurodegenerative disease with the support of my mentor, Dr. Murray Grossman, and my co-mentors, Dr. John Trojanowski and Dr. Lyle Ungar. Specifically, with Dr. Trojanowksi I will engage in training related to biofluid and genetic biomarkers of FTLD. I will develop advanced neuroimaging skills and cutting-edge biostatistical methods with Dr. Ungar. Each of these training modalities will be supported by complementary formal coursework, participation in seminars, attendance of conferences, and regularly scheduled meetings with mentorship team. Research: FTLD is a neurodegenerative disease affecting approximately 15 out of 100,000 individuals. In recent years detailed neuropathological investigations at autopsy have demonstrated distinct sources of histopathological abnormalities in FTLD, including the presence of tau inclusions (FTLD-tau) and TDP-43 proteinopathies (FTLD-TDP). However, there are currently no in vivo methods for discriminating between FTLD-tau and FTLD-TDP. There is an urgent need to improve the in vivo diagnosis of FTLD to appropriately enter patients into emerging clinical trials, and to develop sensitive and specific endpoints in trials that can quantify response to these treatments. The overall research aim of this proposal is to develop multimodal methods to improve in vivo diagnosis of FTLD.